UCLan patented research is utilising aptamers, ligand-binding fragments of aptamers, and oligonucleotides for use as agents in the prevention and/or treatments of cancers, and diagnosis of cancers. These agents and methods are particularly useful in brain cancers such as gliomas.
Our Aptamer work concerns the identification, characterisation and application of novel aptamers to malignant cells for diagnosis and treatment.
Aptamers are small and highly structured single stranded DNA or RNA molecules. They have a highly defined three dimensional structure, which helps them to bind with high affinity to targeted molecules with high specificity. Their unique binding properties make them valuable for diagnostics, purification process, target validation, drug discovery and therapeutic interventions. A number of recent studies have used aptamers to identify and selectively target cancer cells, including AS1411 (refractory acute myeloid leukaemia or renal cell carcinoma, NOX-A50 and anti-MUC1 (epithelial cell cancer). These aptamers take advantage of the irregular protein expression on the surface of affected cells.
The worldwide annual incidence of primary brain tumours is approximately 4 per 100 000 males and 3 per 100 000 females while the mortality is approximately 3 per 100 000 males and 2 per 100 00 females (Bondy et al., 2008). Eighty-six percent of these tumours were gliomas, with greater than 50 % being the more malignant grade IV glioblastoma multiforme (GBM).
The current strategies for the diagnosis and treatment of glioma are inadequate. For those patients diagnosed with glioblastoma multiforme, the most malignant and aggressive glioma, there is a less than 5% probability of surviving beyond 5 years with a median survival of approximately 15 months (Bondy et al., 2008).
The major issue with the use of chemotherapy is the side effects incurred by the patient, largely due to non-specific drug effects on healthy cells. Therefore a method to specifically target chemotherapy agents to the tumour cells rather than to healthy cells is required.
Our work relates to aptamers, ligand-binding fragments of aptamers, and oligonucleotides. The work is also aimed at the prevention and/or treatments of cancers, and diagnosis of cancers. The agents and methods used are particularly useful in brain cancers such as glioma.
We have now established the method for systemic evolution ligand exponential (SELEX) using glioma cell lines (U87MG; grade IV tumour and 1321n1; grade II tumour) and a non-tumourigenic glial cell line (SVGp12) using the random aptamer library mentioned above. We have a number of unique aptamer sequences which are currently undergoing the same screening process as the modified Cerchia aptamers.
Although the SELEX process to date has involved cell lines, we intend to further develop the process and use patient tissues as a substitute for cell lines. Tumours are a heterogeneous population of cells and therefore to develop a specific aptamer for diagnosis/ therapy/ drug monitoring then we need to take this into account.
- Aptamers are short stranded oligonucleotide sequences that bind to target ligands with high affinity and specificity. They can be modified to attach other moieties such as fluorescent dyes, chemotherapy agents and therefore can be used as a targeted drug delivery system.
- Aptamers overcome a number of drawbacks by other targeting systems such as antibodies; they are cheaper and relatively easy to isolate; no risk of batch to batch variability; do not involve the use of animals to generate them; non-immunogenic; smaller and thus able to penetrate further into the tissues and they can be easily modified to make them more stable under in vivo conditions.
Attachment is possible to other moieties such as fluorescent dyes, chemotherapy agents and therefore can be used as a targeted drug delivery system.